NR AWHW
AU Kawasaki,Y.; Kawagoe,K.; Chen,C.J.; Doh-ura,K.
TI Effectiveness of an orally administered anti-prion chemical
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions THE-07
PT Konferenz-Poster
AB We reported previously that some amyloid imaging probes or amyloidophilic chemicals developed for diagnosis of Alzheimer's disease are effective as anti-prion chemicals when administered intravenously (J Gen Virol. 2004;85:1785-1790). We have developed and tested new amyloidophilic chemicals with better brain-permeability. We have concluded that relatively longer retention in the brain than that of the chemicals might be also important to improve their effectiveness as anti-prion chemicals (J Neurochem. 2006; in press). Here, we report the anti-prion effectiveness of an orally administered amyloidophilic chemical that was developed originally as a drug candidate for Alzheimer's disease and which possesses satisfactory permeability and relatively longer retention in the brain than the imaging chemicals. This chemical, called compB, inhibits PrPres formation in the cells that are persistently infected with RML prion at a subnanomolar dose, but it is not effective in cells that are infected with Fukuoka-1 prion or 22L prion. When administered orally in a form of the mixture with powder feed from the inoculation to the disease terminal, compB prolonged the incubation times of mice who had been inoculated intracerebrally with RML. Its effectiveness was dependent on the compB dose. The highest dose (300 mg/kg/day) prolonged the incubation period by 2.5 times that of the control. The compB effectiveness was also observed in infected mice when it started from different time points after inoculation, although the better effectiveness depended on the earlier start of administration. Oral compB was also beneficial for mice that had been inoculated intracerebrally with Fukuoka-1 or 22L. The effectiveness in these mice, however, was not so prominent as that in the mice with RML. The mice with 263K prion showed no significantly different incubation times using oral compB. Improvement of the pharmacokinetic parameters of compB seems to be necessary for better efficacy. Furthermore, we must elucidate the mechanism of the prion strain-dependent effectiveness and cope with it. Nevertheless, the findings of this study encourage us to pursue chemotherapy for prion diseases.
AD Y. Kawasaki, K. Doh-ura: Department of Prion Research, Tohoku University Graduate School of Medicine, Sendai, Japan; K. Kawagoe, C.J. Chen: Tokyo R&D Center, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan. E-mail: doh-ura@mail.tains.tohoku.ac.jp
SP englisch
PO Italien